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The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the prot...

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Autores principales: El-Kadi, Ali Morsi, Bros-Facer, Virginie, Deng, Wenhan, Philpott, Amelia, Stoddart, Eleanor, Banks, Gareth, Jackson, Graham S., Fisher, Elizabeth M. C., Duchen, Michael R., Greensmith, Linda, Moore, Anthony L., Hafezparast, Majid
Formato: Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881788/
https://www.ncbi.nlm.nih.gov/pubmed/20382740
http://dx.doi.org/10.1074/jbc.M110.129320
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author El-Kadi, Ali Morsi
Bros-Facer, Virginie
Deng, Wenhan
Philpott, Amelia
Stoddart, Eleanor
Banks, Gareth
Jackson, Graham S.
Fisher, Elizabeth M. C.
Duchen, Michael R.
Greensmith, Linda
Moore, Anthony L.
Hafezparast, Majid
author_facet El-Kadi, Ali Morsi
Bros-Facer, Virginie
Deng, Wenhan
Philpott, Amelia
Stoddart, Eleanor
Banks, Gareth
Jackson, Graham S.
Fisher, Elizabeth M. C.
Duchen, Michael R.
Greensmith, Linda
Moore, Anthony L.
Hafezparast, Majid
author_sort El-Kadi, Ali Morsi
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons.
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spelling pubmed-28817882010-06-10 The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease El-Kadi, Ali Morsi Bros-Facer, Virginie Deng, Wenhan Philpott, Amelia Stoddart, Eleanor Banks, Gareth Jackson, Graham S. Fisher, Elizabeth M. C. Duchen, Michael R. Greensmith, Linda Moore, Anthony L. Hafezparast, Majid J Biol Chem Molecular Bases of Disease Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons. American Society for Biochemistry and Molecular Biology 2010-06-11 2010-04-09 /pmc/articles/PMC2881788/ /pubmed/20382740 http://dx.doi.org/10.1074/jbc.M110.129320 Text en © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Molecular Bases of Disease
El-Kadi, Ali Morsi
Bros-Facer, Virginie
Deng, Wenhan
Philpott, Amelia
Stoddart, Eleanor
Banks, Gareth
Jackson, Graham S.
Fisher, Elizabeth M. C.
Duchen, Michael R.
Greensmith, Linda
Moore, Anthony L.
Hafezparast, Majid
The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title_full The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title_fullStr The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title_full_unstemmed The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title_short The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1(G93A) Mouse Model for Motor Neuron Disease
title_sort legs at odd angles (loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in sod1(g93a) mouse model for motor neuron disease
topic Molecular Bases of Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881788/
https://www.ncbi.nlm.nih.gov/pubmed/20382740
http://dx.doi.org/10.1074/jbc.M110.129320
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